Recent clinical studies have found that HIV infection of the central nervous system results in a CNS dysfunction termed AIDS Dementia Complex (ADC). ADC is characterized by decreased motor speed, impaired concentration, and poor mental manipulation skills. All these symptoms are also seen in the "subcortical dementia" of Parkinson's disease. This suggests that HIV neurotoxicity may result from dopaminergic dysfunction. Preliminary data from our laboratory to support this is, that HIV-derived neurotoxic factor(s): (1) preferentially kill rat embryonic striatal, as opposed to cortical, cell culture explants, and (2) kill monoclonal human neuroblastoma cells that synthesize dopamine (DA) and the DA D1 and D2 receptor subtypes. To further characterize this neurotoxicity, the human neuroblastoma cell lines LA-N-1 and SK-N- MC are utilized due to their dopaminergic properties which can be enhanced following differentiation with the morphogen retinoic acid (RA). LA-N-1 cells have been shown to increase their intracellular content of dopamine, while decreasing their intracellular norepinephrine content following differentiation with RA. Furthermore, SK-N-MC have been shown to contain receptors for both DA D1 and D2 subtypes. We have demonstrated that the DA D2 subtype receptor can be upregulated in the LA-N-1 cells following differentiation with RA, although there does not appear to be any enhancement of D1 or D2 subtype receptors in the SK-N-MC cell line following RA treatment. Co-cultures of HIV-infected human monocytes with U251 human astrocytes were found to secrete a neurotoxic factor(s). Preliminary studies of SK-N-MC cell cultures treated with these factors were found to have a significant decrease (by 50%) in viability. Further studies of this HIV-neurotoxicity in the neuroblastoma cell line(s) model will provide insights into the mechanisms involved in dopaminergic dysfunction of ADC.